Manufacture of therapeutic calcium preparations



Patented June 28, 1932 UNITED sraras PATENT oFFics ERNST ROTHLIN, OF BASE'L, SWITZERLAND, ASSIGNOR TO THE FIRM OF CHEMICAL WORKS FORMERLY SANDOZ, OF BASEL, SWITZERLAND MANI IFAGTURE OF THERAPEUTIC CALCIUM PREPARATiON-Et No Drawing, Application filed September 2%, 1927, Serial No. 222,945, and in Germany Hovcmlser 526, 19%.

The parenteral administration of calcium salts has hitherto been limited to intravenous injection, as the usual, preparations such as calcium chloride combined with urea, mannite sulphonate of calcium and other preparations of this kind are too irriating tor the tissues, when given by intramuscular or subcutaneous injection. This restriction to intravenous administration is generally conm. sidered as a disadvantage, so that the preparation off a suficiently concentrated calcium salt solution which can be injected intramuscularly, l: lust he considered as a progress, as by the use out such a solution the parenteral is administration of calcium is simplified and extended.

lit has been observed that aqueous solutions of calciumgluconate fulfill these requirements. They can be given by intramuscular 2p injection without causing irritation or nee-- rosis. Even the solution of the salt in question alone possesses this surprising property, so that special admixtures are not necessary. Besides lending itself to intramuscular in- 5 iection, calciumgluconate, when compared with calcium chloride and calcium lactate,

possesses the further advantage of a smaller toxicity, calculated on equal calcium contents. This has been proved by intravenous 39 adr i stration to mice and rabbits.

lmgluconate is however only soluble in cold water up to about 3%. This solubility would appear to he too low for therapeutic application, as normally 0.5-1 g. of calcium 3: salt should he administered. The salt is only easily soluble in hot water, but crystallizes out again to a greater extent from a concenotrated solution when standing in the cold-tor some time.

:0 Now, it has been found that completely stable preparations are obtained if concentrated, aqueous solutions of calciumgluconste are prepared and introduced in hot stateflinto hermetically closahle containers (ampullse -15 for instance), which are then sealed and heated thereafter, if necessary repeatedly at certain intervals, until no further crystallization takes place. It is surprising to note, that ampullw thus prepared remain clear even so. when exposed to the cold, and even when continuously and vigorously shaken as hy long transports. The explanation for thisis apparently the fact, that when the solutions are heated in a sealed ampulla, all centres crystallisation are destroyed, so that lay the above described method a supersaturated solution of unexpected stability is obtained, which crystallizes out only some time after opening the ampulla, or more quickly when the ampulla is scratched or the solution. seeded.

Example 100 g. of calciumgluconate are dissolved in 500 com. of distilled water on the water hath,

allowed to cool down to 15 C. and diluted with distilled water to 1 litre. The solution is then rapidly filtered and heated to 50-60" C. At this temperature the solution is tiltered through a sterile Chambcrlandiilter (the entire apparatus is previously heated to 50 C.) and then poured into ampullse in a sterile space in the normal way. After sealing, the ampullac are heated three times during half an hour, at intervals of Q-Zi days, in a current of steam. Ampullse containing the strongly supersaturated 10% solution of calciumgluconate, thus prepared, have re mained clear during many months.

hat l claim is: I

1. A. process forthe preparation of supersaturated aqueous solutions oi calcium gluconate, comprising the steps of preparing a hot, concentrated calcium gluconate solution, filtering it at 50fi0 (l, introducing the hot solution. into suitable containers and heat ing same in order to destroy centers of crystallisation, after closing, repeatedly by tervals at a, temperature of 70408 6,, until on cooling and vigorously shaking the solutions remain clear.

2. A. process torthe preparation of saturated aqueous solutions of column gluconate, comprising the steps of prey ring a hot, concentrated calcium gluconate solution, filtering it at 50-60" C, introducing the hot solution into suitable containers and heat in same in order to destroy centers of crys ta iaation, after closing, three times for two till Elli

hours at intervals of two days, at a temperature of 70100 C. v

3. As new compositions of matter, clear, stable, sterile and supersaturated aqueous" calcium gluconate\ solutions, containing 440% of calcium gluconate, which possess excellent therapeutical properties and may be used for intramuscular injections free from irritation of the tissues.

In witness whereof I have hereunto signed my name this 19th dag of Se tember, 1927.

' RNS ROTHLIN. 

